Cinnoline, reduction

Surprisingly, no fully detailed syntheses of pyridopyridazines by joining of two heteroatoms have been recorded, although a recent patent claimed the preparation of pyrido-[2,3-c]-, -[3,2-c]-, -[3,4-c]- and -[4,3-c]cinnolines by reduction of 2,2 -dinitro substituted phenylpyridines with a variety of reagents (80GEP2939259). 

CINNOLINES AND QUINOXALINES Replacement of a methine in oxolinic acid (46) by nitrogen is apparently consistent with retention of antibacterial activity. One approach begins with reduction of nitroacetophenone 144 to afford the corresponding aminoketone (145). Treatment of this intermediate with nitrous acid leads to the diazonium salt the diazonium group condenses with the ketone methylene group (as its enol form) to lead to the cyclized product, cinnoline 147. Bromination proceeds at the position adjacent the enol grouping (148) ... 

Fig. 14 Reduction of PhjCSPh by electrochemically generated aromatic anion radicals (in DMF at 25°C). Variation of the rate-determining step rate constant, A , with the standard potential of the aromatic anion radical, p,g (from left to right azobenzene, benzo[c]cinnoline, 4-dimethylaminoazobenzene, terephthalonitrile, naphthacene, phlhalonitrile, perylene, fluoranthene, 9,10-diphenylanthracene). The dotted lines are the theoretical limiting behaviours corresponding to the concerted (right) and stepwise (left) pathways. (Adapted from Severin et al 1988.)...

Catalytic reduction of ll-mercaptopyrido[l,2-6]cinnolin-6-ium hydroxide inner salt (41) over Raney Ni yielded 2-(2-aminobenzyl)pyridine (74JHC125). When a 36-h reaction period was applied in the hydrolysis of 42, 1-benzylisoquinoline was obtained (83JOC1084). 

Ring-opened products were obtained from pyrido[l,2-6]cinnolin-6-ium hydroxide inner salt (17, R = H) by oxidation with 3-chloroperoxybenzoic acid, or by reduction with Zn in acetic acid, and from the 5-methyl derivative 43 by reduction with Zn in acetic acid (74JHC125). 

A variation of this procedure is given in Preparation 3-3, in which a mixed solvent is used in the preparation of benzo[c]cinnoline by a lithium aluminum hydride reduction [67]. 

Preparation of Benzo[c]cinnoline by Lithium Aluminum Hydride Reduction. 316... 

Reduction of aromatic nitro compounds,2 Aromatic compounds arc reduced to anilines in 90 95% yield by TiCl, (8 equivalents) and HOAc-H20 (1 1, v/v) at room temperature (7 minutes). Nitro derivatives of quinoline, isoquinolinc, and cinnoline are reduced under the same conditions. 

It was previously mentioned1 that cinnoline and 3-substituted cinnolines (94) could be prepared from the condensation products (95) between an o-nitrobenzaldehyde and a nitroalkane by electrochemical reduction. The reaction has been further studied,138 and it was noticed that when the reduction was carried out stepwise, anthranils (96) were formed, especially at elevated temperatures. The final ring closure was catalyzed by traces of oxygen, whereas too much oxygen produced the cinnoline JV-oxide (97) the ring closure was believed to be a radical chain reaction where the formation of the aromatic cinnoline was part of the driving force [Eq. (76)]. 

The reductions of cinnolines and phthalazines were discussed in Part I, Section IV,B (Ring Contractions) or V,D. 1-Methylisoindole (190) has since been isolated as a hydrochloride from reduction in hydrochloric acid of 1-methylphthalazine with strict control of the potential to avoid further reduction to methylisoindoline (191). Purification requires acidic conditions the free base turned quickly to a tar299,300 [Eq. (113)]. 

Quinoline 1-oxides can be rearranged photochemically into indoles (103 — 104 — 105) or N-hydroxyindoles (106 — 107). Cinnolines are reductively ring-contracted into indoles (Section 3.2.1.6.9.ii). 

Controlled reduction of 2,2 -dinitrobiphenyl is achieved with 2, 1, and 0.5 molar equivalents of sodium borohydride in the presence of palladium on carbon and sodium hydroxide to give benzo[c]cinnoline, its /V-oxide, and AT V -dioxide, respectively, in high yields (Scheme 6). 

A number of cinnolines have been obtained by alkali treatment of isatins. Thus, 214 gave 215,88-70 while isatin on treatment with base followed by hydrogen and palladium, diazotization, and reduction gave 3-hydroxycinnoline.62 4... 

Oxazines, which are readily prepared from enamines and a-bromokctoximes, are reductively converted to pyrroles in good yields by iron carbonyls (Scheme 116) (81CL869). The reductive conversion of cinnolines to indoles or indolines (71JCS(C)3088> and of phthalazines to isoindoles or phthalimidines (70ACS1867) may occasionally be of synthetic value. 

The reduction of compounds suitably substituted with reducible functional groups can be advantageously used for the preparation of heterocyclic ring systems 15 5 The guiding principle here is to form a nucleophilic center in the molecule by cathodic reduction of a functional group and then have this to react with an electrophilic center (which may also be formed in an electrochemical process or be present in the starting material) suitably positioned for ring closure. Thus, 2,2-dinitrobiphenyl can be reduced to benzo[c] cinnoline in acid solution ... 

By controlling the potential the reaction can be stopped at the N-oxide stage at more negative potentials the reduction can be controlled to give either benzo[c]cinnoline or its dihydro derivative. 

In the synthesis of symmetrically 3,8-disubstituted benzo[c]cinnolines 52 from the corresponding 4,4-disubstituted 2,2-dinitrobiphenyls 51, acetophenone has been used as reductant in a basic solution (Scheme 26) 2-nitroso-2-hydroxylaminobiphenyls are assumed to be intermediates in this reaction <2004JOC7720, CHEC-III(8.01.9.1)73>. 

Dinitrobiphenyl (57)44 88 is thus reducible in alkaline solution at a suitable potential to benzo[c]cinnoline N-oxide (58) in acid solution the reduction proceeds to 4,5-dihydrobenzo[c]cinnoline (59) which is very easily oxidized, e.g., by air, to benzo[c]cinnoline (60). 

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